CN116969943A - Tri-cyclic diacylglycerol kinase inhibitors and uses thereof - Google Patents
Tri-cyclic diacylglycerol kinase inhibitors and uses thereof Download PDFInfo
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- CN116969943A CN116969943A CN202310460995.9A CN202310460995A CN116969943A CN 116969943 A CN116969943 A CN 116969943A CN 202310460995 A CN202310460995 A CN 202310460995A CN 116969943 A CN116969943 A CN 116969943A
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- alkyl
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- amino
- carboxyl
- cyano
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- 239000003047 diacylglycerol kinase inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 8
- -1 cyano, hydroxyl Chemical group 0.000 claims description 426
- 125000000217 alkyl group Chemical group 0.000 claims description 167
- 125000003545 alkoxy group Chemical group 0.000 claims description 85
- 229910052736 halogen Inorganic materials 0.000 claims description 69
- 150000002367 halogens Chemical class 0.000 claims description 69
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 61
- 108010062677 Diacylglycerol Kinase Proteins 0.000 claims description 58
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 54
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 48
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 48
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 45
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 38
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 36
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 29
- 108010058222 Deoxyguanosine kinase Proteins 0.000 claims description 29
- 102100022732 Diacylglycerol kinase beta Human genes 0.000 claims description 29
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 29
- 239000000460 chlorine Substances 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 239000011737 fluorine Substances 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 28
- 229910052794 bromium Inorganic materials 0.000 claims description 28
- 102000011107 Diacylglycerol Kinase Human genes 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 20
- 125000002883 imidazolyl group Chemical group 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 17
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 17
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 17
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 17
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
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- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 239000013543 active substance Substances 0.000 claims description 4
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- 229940123948 Diacylglycerol kinase inhibitor Drugs 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 9
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- 125000006413 ring segment Chemical group 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a compound of a tricyclic diacylglycerol kinase inhibitor, pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt or stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or stereoisomer thereof, and a method for preparing the compound, the pharmaceutically acceptable salt or stereoisomer thereof into medicinesIs provided.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound which can be used as a diacylglycerol kinase inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof in preparing medicines for treating and/or preventing diseases mediated by diacylglycerol kinase and related diseases.
Background
Developing safe and effective cancer treatments is one of the most challenging problems faced by modern medicine. Early treatment methods included chemotherapy and surgical treatment. Chemotherapy is mostly not specific, adverse reactions and drug resistance are easy to occur after long-term use, and immunotherapy is recently receiving attention. The immune system can be utilized to recognize and attack tumors by immune checkpoint inhibitors, CTLA-4 and PD-1 being referred to as immune checkpoint molecules. Immunotherapy with anti-PD-1 antibodies has shown significant clinical effectiveness in various cancers, including melanoma and non-small cell lung cancer, and other applications are expanding.
The diacylglycerol kinase family (DGKs) plays an important role in signal transduction by regulating the balance between the two lipid signals Diacylglycerol (DAG) and Phosphatidic Acid (PA). The 10 kinases of the mammalian DGK family are divided into 5 different subtypes according to different genotypes (Merida, i., et al biochem.j. (2008) 409 (1), 1-18). Three DGK subtypes (dgkα, dgkδ and dgkζ) are known to exist in T cells, but only two dgkα and dgkζ are thought to play important roles in promoting DAG metabolism downstream of the TCR, depending on type I (α, β, γ), type II (δ, η, κ), type III (ε), type IV (ζ, iota), type V (θ). DGKα/ζ is distributed in both nucleus and cell membrane, and is activated by Src and other regulator and transferred to plasma membrane, DAG phosphorylation is converted into PA, which regulates the decrease or activation of expression of mTOR, HIF-1α and other tumor downstream pathways (Carrasco, S., et al mol. Biol. Cell (2004) 15 (6), 2932-2942). DGK inhibition not only interferes with oncogenic pathways to directly kill tumor cells, but also can restore immune tumor attack.
In T cells, when the TCR interacts with the major histocompatibility gene complex (pMHC), and in the presence of the co-stimulatory signal CD28, TCR proximal PTKs are activated and result in recruitment of molecules. Activation of phospholipase cγ1 (plcγ1) can hydrolyze phosphatidylinositol-4, 5-bisphosphate (PIP 2) on membranes to form the second messengers (inositol triphosphate) IP3 and DAG. IP3 activated Ca 2+ The CaN-NFAT pathway, while the DAG activates the Ras-ERK-AP1 and NF-kB pathways. DGKs inhibit DAG-mediated signals by converting DAG to PA. Selective IP3-Ca 2+ The NFAT signal induces T cells into an anergic (anergy) state in the presence of a weak DAG-mediated signal (Power, N.A., et al Nat. Immunol (2000) 1:317-321). T cell anergy refers to a decrease in co-stimulatory signals upon antigen recognition that results in T cells becoming functionally inactive.
DGK expression dysregulation is associated with a variety of pathologies, including chronic inflammation, tumor immune evasion responses, and immunodeficiency diseases. The biological roles of dgkα and ζ isomers in immune cell differentiation and effector function are of great interest. Recent studies suggest that upregulation of dgkα and ζ may be one of the mechanisms by which tumors induce T cell tolerance. The mouse models of knockout of DGK alpha and zeta show a highly sensitive T cell phenotype and are anti-tumor immune active and suggest that both DGK alpha and zeta are simultaneously more immune responsive than DGK zeta alone (Riese M.J.et al J.biol. Chem, (2011) 7:5254-5265; in-Young, J.; et al cancer Research (2018): canres.0030.2018; olencdock, B.A.; et al Nat. Immunol.; 2006) 7:1174-1181;Zha,Y.et al.Nat.Immunol.; 2006) 7:1166-1173;Baldanzi,G.et al.Clin.Sci.; lond.; 2020) 134:1637-1658; merida, I.; et al V.Adgul.; 2017:63:22-31.). Inhibition of dgkα and/or dgkζ is a promising approach to anti-tumor immunotherapy.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and can be used as an inhibitor of DGK alpha, DGK zeta or both DGK alpha and DGK zeta. Furthermore, the compounds can be used for treating or preventing diseases or related diseases mediated by abnormal activities of DGK alpha, DGK zeta or both DGK alpha and DGK zeta, such as proliferative diseases (benign tumors or cancers).
The specific technical scheme is as follows:
in one aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof,
wherein,,
X 1 、X 2 are independently selected from CR 4 Or N;
represents a single bond or is absent; when it indicates absence, X 3 Selected from C, CH or N; when representing a single bond, X 3 Is C;
ring A is selected from optionally 1 to 4Q 1 Substituted 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-8 membered heteroaryl;
R 1 selected from-CH 2 R a 、-CHR a R b 、-CR a R b R c or-NR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each R 4 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each R a Each R b Each R c Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted C 1-6 Alkyl, C 1-6 Alkoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-8 membered heteroaryl, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m and each n are each independently an integer of 0 to 4;
each t is independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
X 1 、X 2 are independently selected from CR 4 Or N;
represents a single bond or is absent; when it indicates absence, X 3 Selected from C, CH or N; when representing a single bond, X 3 Is C;
ring A is selected from optionally 1 to 4Q 1 Substituted 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;
R 1 selected from-CH 2 R a 、-CHR a R b 、-CR a R b R c or-NR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R 4 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R a Each R b Each R c Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted C 1-4 Alkyl, C 1-4 An alkoxy group, an amino group,each Q2 is independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-6 membered heteroaryl, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
X 1 、X 2 Are independently selected from CR 4 Or N;
represents a single bond or is absent; when it indicates absence, X 3 Selected from C, CH or N; when representing a single bond, X 3 Is C;
ring A is selected from optionally 1 to 3Q 1 Substituted cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-trisOxazolyl, 1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl or 1,2,4, 5-tetrazinyl;
R 1 selected from-CH 2 R a or-CHR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridazinyl, oxazolyl, isoxazolyl or pyrazinyl optionally substituted with 1 to 2 substituents each independently selected from carboxy, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R 4 Each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q 1 Independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoroMethoxy;
each R a Each R b Each R c Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-6 membered heteroaryl, each Q 3 Each independently selected from halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2.
In certain embodiments, the compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof, have structures of formula (II-1), formula (II-2), formula (II-3),
wherein,,
X 1 each independently selected from CH or N;
ring A is selected from optionally 1 to 3Q 1 Substituted 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;
R 1 Selected from-CH 2 R a 、-CHR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R a Each R b Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 3Q 2 Substituted C 1-4 Alkyl, C 1-4 Alkoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl or- (CH) 2 ) t -a 5-6 membered heteroaryl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1,2 or 3;
each t is independently selected from 0, 1 or 2;
-represents a single bond or is absent.
In certain embodiments, the compounds of the foregoing general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein,
ring A is selected from optionally 1 to 3Q 1 Substituted pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl;
R 1 selected from-CH 2 R a or-CHR a R b ;
Each R 2 Each R 3 Independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, fluoro, chloro, bromo, iodo, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridazinyl, oxazolyl, isoxazolyl or pyrazinyl optionally substituted with 1 to 2 substituents each independently selected from carboxy, cyano, hydroxy, nitro, amino, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each R 4 Are each independently selected from the group consisting of hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, fluoro,Chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q 1 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each R a Each R b Each R c Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, each Q 2 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano,
Or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-6 membered heteroaryl, each Q 3 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1,2 or 3;
each t is independently selected from 0, 1 or 2.
In certain embodiments, the ringA is selected from optionally 1-2Q 1 Substituted pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; preferably, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted as follows:
each Q 1 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted 4, 5-dihydroimidazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl or 1,2, 4-triazolyl; preferably, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted as follows: each Q 1 Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxyA radical, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, R 1 Selected from-CH 2 R a 、-CHR a R b ;
Each R a Each R b Independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,
Or optionally 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -pyridinyl, - (CH) 2 ) t Pyrimidinyl, - (CH) 2 ) t Pyridazinyl, - (CH) 2 ) t -pyrazinyl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl.
In certain embodiments, R 1 Selected from-CH 2 R a 、-CHR a R b ;
Each R a Each independently selected from hydrogen, halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or optionally by 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -a 5-6 membered heteroaryl;
each R b Each independently selected from optionally 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -a 5-6 membered heteroaryl;
each Q 3 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl.
In certain embodiments, R 1 Selected from-CH 2 R a 、-CHR a R b ;
Each R a Each independently selected from hydrogen, halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or optionally by 1 to 3Q 3 Substituted phenyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl;
each R b Each independently selected from optionally 1 to 3Q 3 Substituted phenyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl;
each Q 3 Independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethylA radical, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl.
In certain embodiments, each R 2 Each R 3 Independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen or C optionally substituted with 1-2 substituents 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group.
In certain embodiments, each R 2 Each R 3 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, oxetanyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl optionally substituted with 1-2 substituents; the substituents are each independently selected from carboxyl, cyano, hydroxyl, nitro, amino, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R 2 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, oxetanyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl optionally substituted with 1-2 substituents; the substituents are each independently selected from carboxyl, cyano, and hydroxyNitro, amino, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R 3 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, the compounds of the foregoing general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein,
Ring A is selected from optionally 1-2Q 1 Substituted pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; preferably, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted as follows:
each Q 1 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R 1 selected from-CH 2 R a 、-CHR a R b ;
Each R a Each independently selected from hydrogen, halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or optionally by 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -a 5-6 membered heteroaryl;
each R b Each independently selected from optionally 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -a 5-6 membered heteroaryl; each Q 3 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each R 2 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, oxetanyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl optionally substituted with 1-2 substituents; the substituents are each independently selected from carboxyl, cyano, hydroxyl, nitro, amino, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each R 3 Are respectively and independently selected fromHydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each R 4 Each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2.
In certain embodiments, R 1 Selected from the following groups:
wherein Y is 1 、Y 2 Each independently selected from CH or N;
each R a Independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each p, each q is independently selected from 0, 1, 2 or 3.
In certain embodiments, R 1 Selected from the following groups:
wherein each Y 1 Each Y 2 Each independently selected from CH or N;
each R a Each independently selected from hydrogen, halogen, amino, hydroxy, carboxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q 3 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
Each p, each q is independently selected from 0, 1,2 or 3.
In certain embodiments, the compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof, have structures of formula (III-1), formula (III-2), formula (III-3),
wherein,,
X 1 each independently selected from CH or N;
each Y 1 Each Y 2 Each independently selected from N or CH; each p, each q is independently selected from 0, 1 or 2;
ring A, each R 2 、R 3 、Q 1 Each Q 3 And are defined in any of the preceding embodiments.
In certain embodiments, the compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof, have structures of formula (IV-1), formula (IV-2), formula (IV-3),
wherein,,
X 1 each independently selected from CH or N;
each Y 1 Each Y 2 Each independently selected from N or CH;
ring A, each R 2 、R 3 、Q 1 Each Q 3 And are defined in any of the preceding embodiments.
In certain embodiments, the compounds of the foregoing general formula (III-1), general formula (III-2), general formula (III-3), general formula (IV-1), general formula (IV-2), general formula (IV-3), pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein,
ring A is selected from optionally 1-2Q 1 Substituted 4, 5-dihydroimidazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl or 1,2, 4-triazolyl; preferably, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted as follows:
each Q 1 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxyA cyclopropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy group;
each R 2 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, oxetanyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl optionally substituted with 1-2 substituents; the substituents are each independently selected from carboxyl, cyano, hydroxyl, nitro, amino, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each R 3 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q 3 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, cyano, hydroxyl, nitro, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Y 1 Each Y 2 Each independently selected from N or CH;
each p, each q is independently selected from 0, 1 or 2.
In certain embodiments, X 1 Each independently is N.
In certain embodiments, ring A is selected from the group consisting of optionally 1-2Q 1 Substituted as follows: each Q 1 Each independently selected from hydrogen, fluorine, chlorine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R 2 Are each independently selected from fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group; preferably, each R 2 Each independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R 3 Are each independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group; preferably, each R 3 Each independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy.
In certain embodiments, each R 3 Are independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group; preferably, each R 3 Each independently selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy.
In certain embodiments, each Q 3 Are independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group; preferably, each Q 3 Each independently selected from fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.
Any substituent groups in any embodiment of the invention can be mutually combined, and the combined technical scheme is still included in the protection scope of the invention.
In some embodiments of the invention, the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof has the structure:
the "pharmaceutically acceptable salt" as used herein refers to addition salts of pharmaceutically acceptable acids and bases, such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, salts with inorganic acids, salts with acidic amino acids or basic amino acids, and the like.
"stereoisomers" as used herein refers to compounds of the invention which contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the aforementioned formula (I), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV-1), formula (IV-2), formula (IV-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form.
In some embodiments of the invention, the above-described pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation arts, and the choice of the particular carrier and/or diluent will depend on the mode of administration or type and state of disease for the particular patient being treated. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts. For example, pharmaceutically acceptable carriers and/or diluents may include solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, binders, lubricants, stabilizers, hydration agents, emulsifying accelerators, buffers, absorbents, colorants, ion-exchange agents, mold release agents, coating agents, flavoring agents, antioxidants and the like which are conventional in the pharmaceutical arts. Flavoring agent, antiseptic, sweetener, etc. can be added into the pharmaceutical composition if necessary.
In another aspect, the invention also provides the use of a compound of the general formula (I), the general formula (II-1), the general formula (II-2), the general formula (II-3), the general formula (III-1), the general formula (III-2), the general formula (III-3), the general formula (IV-1), the general formula (IV-2), the general formula (IV-3), pharmaceutically acceptable salts or stereoisomers thereof, the pharmaceutical preparation or the pharmaceutical composition in the preparation of a medicament for treating and/or preventing diseases mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta; the diseases mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta and related diseases are selected from cancers or benign tumors.
The invention also provides application of the compounds shown in the general formula (I), the general formula (II-1), the general formula (II-2), the general formula (II-3), the general formula (III-1), the general formula (III-2), the general formula (III-3), the general formula (IV-1), the general formula (IV-2), the general formula (IV-3), pharmaceutically acceptable salts or stereoisomers thereof, the medicinal preparation or the medicinal composition in treating/preventing diseases mediated by abnormal activities of DGK alpha, DGK zeta or both DGK alpha and DGK zeta; the diseases mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta and related diseases are selected from cancers or benign tumors.
In another aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned formula (I), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV-1), formula (IV-2), formula (IV-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more second therapeutically active agents, optionally further comprising one or more pharmaceutically acceptable carriers and/or diluents.
The present invention relates to a pharmaceutical composition comprising the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III-1), general formula (III-2), general formula (III-3), general formula (IV-1), general formula (IV-2), general formula (IV-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which can be administered alone or in combination with one or more second therapeutically active agents for use in combination with the compound of the present invention in the treatment and/or prevention of diseases mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta.
In certain embodiments, the second therapeutically active agent is selected from the group consisting of anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cytostatic agents, immune checkpoint inhibitors, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody.
The present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV-1), formula (IV-2), formula (IV-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a pharmaceutical formulation of the foregoing, or a pharmaceutical composition of the foregoing, wherein the disease is dgkα, dgkζ, or a disease mediated by abnormal activity of both dgkα and dgkζ, and related diseases; the diseases mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta and related diseases are selected from cancers or benign tumors.
Cancers described herein include, but are not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female genital tract cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.
In the description and claims of the present application, compounds are named according to chemical structural formulas, and if the same compound is represented, the named and chemical structural formulas of the compounds are not identical, the chemical structural formulas are used as references.
In the present application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present application, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present application are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present application is in control.
"halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
"halo" as used herein means that any hydrogen in a substituent may be substituted with one or more of the same or different halogens. "halogen" is as defined above.
"C" as described in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-5 Alkyl "," C 1-4 Alkyl "," C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-6 Alkyl "," C 2-5 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl "," C 3-6 Alkyl "," C 3-5 Alkyl "," C 3-4 Alkyl "," C 4-6 Alkyl "," C 4-5 Alkyl "," C 5-6 Alkyl ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. The book is provided withThe invention is described as "C 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkylene "means C as described above 1-6 Alkyl groups having one hydrogen atom removed to form groups, including, for example, "C 1-5 Alkylene "," C 1-4 Alkylene "," C 1-3 Alkylene "," C 1-2 Alkylene "," C 2-6 Alkylene "," C 2-5 Alkylene "," C 2-4 Alkylene "," C 2-3 Alkylene "," C 3-6 Alkylene "," C 3-5 Alkylene "," C 3-4 Alkylene "," C 4-6 Alkylene "," C 4-5 Alkylene "," C 5-6 Alkylene ", and the like, specific examples include, but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like. "C" as described in the present invention 1-4 Alkylene "means C 1-6 Specific examples of the alkylene group include those having 1 to 4 carbon atoms.
"C" as described in the present invention 2-6 Alkenyl "refers to straight-chain or branched or cyclic alkenyl groups of 2 to 6 carbon atoms containing at least one double bond and includes, for example," C 2-5 Alkenyl "," C 2-4 Alkenyl "," C 2-3 Alkenyl ", and the like, specific examples include, but are not limited to: ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 2, 3-dimethyl-2-3-butenyl, 2, 3-ethyl-2-butenyl, 2-methyl-3-butenyl, 2-ethyl-2-butenyl, and the like.
"C" as described in the present invention 2-6 Alkynyl "isRefers to straight or branched chain alkynyl groups of 2 to 8 carbon atoms containing triple bonds, including for example "C 2-5 Alkynyl "," C 2-4 Alkynyl "," C 2-3 Alkynyl ", and the like, specific examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, and the like.
"C" as described herein 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, C 1-6 Alkylaminoacyl, C 1-6 Alkylamido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl "means C 1-6 alkyl-O-, C 1-6 alkyl-NH- (C) 1-6 Alkyl group 2 -N-、C 1-6 alkyl-NH-C (O) -, C 1-6 alkyl-C (O) -NH-, C 1-6 alkyl-S (O) 2 -、C 1-6 alkyl-S (O) 2 -NH-、C 1-6 alkyl-NH-S (O) 2 -、C 1-6 alkyl-C (O) -, C 1-4 alkyl-O-C (O) -formed radicals, where "C 1-6 The definition of alkyl "is as described above.
"C" as described herein 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, C 1-4 Alkylaminoacyl, C 1-4 Alkylamido, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl "means C 1-4 alkyl-O-, C 1-4 alkyl-NH- (C) 1-4 Alkyl group 2 -N-、C 1-4 alkyl-NH-C (O) -, C 1-4 alkyl-C (O) -NH-, C 1-4 alkyl-S (O) 2 -、C 1-4 alkyl-S (O) 2 -NH-、C 1-4 alkyl-NH-S (O) 2 -、C 1-4 alkyl-C (O) -, C 1-4 alkyl-O-C (O) -formed radicals, where "C 1-4 The definition of alkyl "is as described above.
"halo C" as described herein 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, halogenated C 1-6 Alkylene, halogenated C 1-6 Alkoxy "means that one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxy, amino, carboxy groups, respectively, are substituted for C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by a hydrogen atom in an alkoxy group.
"halo C" as described herein 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkylene, halogenated C 1-4 Alkoxy "means that one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxy, amino groups are substituted for C, respectively 1-4 Alkyl, C 1-4 Alkylene, C 1-4 A group formed by a hydrogen atom in an alkoxy group.
"3-12 membered cycloalkyl" as used herein refers to a saturated or partially saturated cyclic alkyl group having 3 to 12 carbon atoms and having no aromaticity, and includes "monocycloalkyl" and "condensed ring alkyl".
"monocycloalkyl" as used herein refers to a saturated or partially saturated and non-aromatic monocycloalkyl group, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "4-7 membered saturated cycloalkyl", "4-8 membered saturated cycloalkyl", "5-7 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl", "3-6 membered partially saturated cycloalkyl", "4-7 membered partially saturated cycloalkyl", "4-8 membered partially saturated cycloalkyl", "5-7 membered partially saturated cycloalkyl", "5-6 membered partially saturated cycloalkyl", etc. Specific examples of the "3-8 membered saturated cycloalkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctyl (cyclooctyl), and the like; specific examples of the "3-8 membered partially saturated cycloalkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, cyclohex-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl, and the like.
The term "fused ring alkyl" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms, wherein one ring of the fused ring may be an aromatic ring, but the whole fused ring has no aromaticity; the fusing mode can be as follows: 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, and the like. Examples include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, decatetrahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3 a-tetrahydropentalenyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3, 4a,5,6, 4 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4, 6,7,8, 10-benzopentalenyl, benzocyclohexyl, benzopentalenyl, and the like.
"3-12 membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic or fused ring group containing at least one heteroatom (e.g., containing 1,2,3,4 or 5) and having 3 to 12 ring atoms, which is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-12 membered heterocyclic group" as used herein includes "3-12 membered saturated heterocyclic group" and "3-12 membered partially saturated heterocyclic group". Preferably, the "3-12 membered heterocyclic group" according to the present invention contains 1 to 3 hetero atoms; preferably, the "3-12 membered heterocyclic group" according to the present invention contains 1 to 2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-12 membered heterocyclic group" according to the present invention contains 1 to 2 nitrogen atoms. The "3-12 membered heterocyclic group" is preferably "3-10 membered heterocyclic group", "3-8 membered heterocyclic group", "4-8 membered heterocyclic group", "3-6 membered saturated heterocyclic group", "3-6 membered nitrogen-containing heterocyclic group", "3-6 membered saturated nitrogen-containing heterocyclic group", "5-6 membered saturated heterocyclic group" or the like. Specific examples of "3-12 membered heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazabicycloalkyl, 3H-diazacyclyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxanyl, 1, 2-oxazinyl, 1, 4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl 2H-pyran-2-one, 3, 4-dihydro-2H-pyranyl, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzopyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridocyclohexyl, pyridoxazolidines, pyridothiazolidines, pyridoisoxazolidines, pyridoisothiazolidines, pyridopiperidines, pyridomorpholines, pyridopiperazines, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidoetetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidines, pyrimidothiazidines, pyrimidoisoxazolidines, pyrimidoidithiazolidines, pyrimidopiperidyl, pyrimidohorminyl, pyrimidopiperidinyl, pyrimidoetetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromene-2-onyl, 4H-chromene, 4H-chromen-4-onyl, 4H-1, 3-benzoxazolyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazoyl, hexahydrofuroimidazoyl, 4,5,6, 7-tetrahydro-1H-benzo [3,4-d ] imidazolyl, octahydro-pyrrolo [3,4-d ] pyrrolyl, and the like.
The "6-10 membered aryl" as used herein refers to an aromatic cyclic group containing 6-10 ring carbon atoms, and includes "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl".
"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The term "8-to 10-membered condensed ring aryl" as used herein refers to an unsaturated, aromatic cyclic group containing 8 to 10 ring carbon atoms, preferably "9-to 10-membered condensed ring aryl", which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, and specific examples thereof are naphthyl and the like.
The term "5-12 membered heteroaryl" as used herein refers to a cyclic group having an aromatic nature and containing 5 to 12 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom), and may be, for example, a 5-12 membered nitrogen-containing heteroaryl, a 5-12 membered oxygen-containing heteroaryl, a 5-12 membered sulfur-containing heteroaryl, etc. Including "5-8 membered single heteroaryl" and "8-10 membered fused heteroaryl".
"5-8 membered mono-heteroaryl" as used herein refers to an aromatic monocyclic ring group containing 5-8 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered mono-heteroaryl" includes, for example, "5-7 membered mono-heteroaryl", "5-6 membered nitrogen containing mono-heteroaryl", "5-nitrogen containing mono-heteroaryl", and the like. Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazinoheptenyl, azocyclotetraenyl and the like. The "5-6 membered heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic ring structure containing 8 to 10 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which may be fused in such a manner as to be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrazolopyrroles, pyrazolothiophenes, furanthiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The term "optionally substituted by …" as used herein includes both "substituted" and "unsubstituted".
The term "therapeutically effective amount" as used herein refers to an amount of a compound, pharmaceutical formulation, pharmaceutical composition, as described above, that is capable of at least alleviating the symptoms of a disorder in a patient when administered to the patient. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances including, but not limited to, the particular disorder being treated, the severity of the disorder, the physical and health of the patient, and the route of administration. The skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.
Advantageous effects of the invention
(1) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has excellent DGK alpha and/or DGK zeta inhibition activity, and can treat and/or prevent diseases and related diseases related to abnormal DGK alpha and/or DGK zeta activity;
(2) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has good pharmacokinetic properties, longer action and high bioavailability;
(3) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has good safety;
(4) The compound has the advantages of simple preparation process, high purity of the medicine, stable quality and easy mass industrial production.
The advantageous effects of the compounds provided by the examples of the present invention are further illustrated by the experiments below, but this should not be construed as the compounds provided by the examples of the present invention only have the following advantageous effects.
Biological Experimental example
Experimental example 1: in vitro enzymatic Activity of the Compounds of the invention
Test article: the structural formula and the preparation method of the compound are shown in the preparation example.
Experimental reagent:
reagent(s) | Manufacturer' s | Goods number |
ADP-Glo Kinase Assay | Promega | V9102 |
DGKα | Signalchem | D21-10BG-10 |
DGKζ | Signalchem | D30-10G-10 |
(5Z,2E)-CU-3 | MCE | HY-121638A |
DLG(Dilauroyl-sn-glycerol) | Signalchem | D430-59 |
ATP | Signalchem | V910B |
DMSO | Sigma | D8418 |
The experimental method comprises the following steps:
1. dilution of the Compounds
1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.
2) The test stock was now diluted 10-fold to 1mM and the 1mM compound solution was diluted 5-fold in a gradient to 10 concentrations, the highest concentration being 1mM.
3) The diluted compounds of the invention were transferred separately to 384 well plates using Echo550, diluted 1000-fold, with 2 duplicate wells per concentration set and DMSO final concentration of 0.1%.
4) The final concentrations of the test compounds were 1000nM, 200nM, 40nM, 8nM, 1.6nM, 0.32nM, 0.064nM, 0.0128nM, 0.00256nM, 0.000512nM.
2. Enzyme reaction experiment
1) 1 Xenzyme buffer was prepared by adding 4 volumes of distilled water to 1 volume of 5 Xenzyme buffer, and 0.1M dithiothreitol was added.
2) Compound dilutions were transferred into each well of the assay plate using Echo 550;
3) The assay plate was sealed and centrifuged for 1 min.
4) The 2 Xenzyme was prepared with 1 Xenzyme buffer.
5) 2.5. Mu.L of 2 Xenzyme was added to 384 well assay plates.
6) The assay plates were centrifuged for 30 seconds and incubated at room temperature for 10 minutes.
7) A mixture of 2 Xsubstrate and ATP was prepared with 1 Xenzyme buffer.
8) The reaction was started by adding 2.5. Mu.L of a 2 Xsubstrate and ATP mixture to 384 well assay plates.
9) Centrifuging for 30 seconds. The assay plates were incubated at room temperature for 2 hours after sealing.
10 4. Mu.L of ADP-Glo reagent was added and incubated at room temperature for 40 minutes.
11 8. Mu.L of enzyme detection reagent was added and incubated at room temperature for 40 minutes.
3. Result detection
1) Chemiluminescent signals were read on an Envision 2104 plate reader.
2) Data is collected.
4. Data analysis
Inhibition (% inh) was calculated using the following formula:
inhibition(%)=100-(Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )
wherein Signal Ave_VC The representation is: luminescence signal intensity of positive control wells without compound;
Signal Ave_PC the representation is: luminescence signal intensity of negative control wells without substrate;
Signal cmpd the representation is: indicating the luminescence signal intensity of the test compound;
calculation of IC using Prism GraphPad 50 .
Experimental results:
TABLE 1 inhibitory Activity of the inventive Compounds against DGK alpha and DGK zeta
Compounds of formula (I) | DGKαIC 50 (nM) | DGKζIC 50 (nM) |
Compound 5 | 4.13 | 77.07 |
Compound 11 | 5.52 | / |
Compound 12 | 7.68 | / |
Compound 17 | / | 52 |
Compound 18 | 0.28 | 16.28 |
In addition, compound 2-3 IC for DGK alpha 50 IC with value less than 50nM for DGK ζ 50 Values less than 0.5 μm; IC of Compounds 13-14 against DGK alpha 50 IC with value less than 1. Mu.M for DGK ζ 50 The value is less than 0.2. Mu.M. Thus, from the above experimental results, it can be seen that the compounds of the present invention are effective inhibitors of dgkα/ζ, which are effective inhibitors of dgkα and/or dgkζ.
Detailed Description
The technical solution of the present invention will be described below with reference to specific embodiments, and the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Abbreviations used in the following experiments represent the following meanings:
DIEA: n, N-diisopropylethylamine HCl: hydrogen chloride EA: acetic acid ethyl ester
DMAP: 4-dimethylaminopyridine Tf 2 O: trifluoromethanesulfonic anhydride DIEA: n, N-dimethylformamide
MeOH: methanol DCM: dichloromethane THF: tetrahydrofuran (THF)
DPPF (DPPF): 1,1' -bis (diphenylphosphine) ferrocene
Intermediate 1: preparation of (2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
2- (bromo (4-fluorophenyl) methyl) -5- (trifluoromethyl) pyridine (12.0 g,36.0 mmol) was dissolved in 200mL of acetonitrile, potassium carbonate (14.9 g,108.0 mmol) and tert-butyl (2S, 5R) -5-ethyl-2-methylpiperazine-1-carboxylate (10.7 g,46.8 mmol) were added, reacted at 80℃for 3 hours, and after completion of the reaction, the solvent was dried, stirred and column chromatography (ethyl acetate: petroleum ether=1:15) was performed to obtain diastereomeric compound intermediate 1A (5.0 g, yield 28.8%) and intermediate 1B (4.0 g, yield 23.1%).
The LC-MS detection method is as follows:
chromatographic column: agilent Eclipse XDB-C18 (2.1X105 mm,5.0 μm);
detection wavelength: 214nm; flow rate: 1.0mL/min; column temperature: 35 ℃;
mobile phase: phase A: 0.02% formic acid-water solution; and B phase: 0.02% formic acid-acetonitrile solution;
gradient conditions:
the detection results are as follows:
preparation example 1: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) - [1,2,4] triazolyl [4,3-a ] [1,5] naphthyridine-7-carbonitrile (preparation of Compound 5)
1. Preparation of (2R, 5S) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine intermediate 1B [ (2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester ] (1.0 g,2.1 mmol) was dissolved in 4N HCl/EA (10 mL), reacted at 15℃for 1 hour, and after the reaction, dried by spin, used directly in the next step.
Preparation of 2.8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -5- (4-methoxybenzyl) -6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile
(2R, 5S) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine (crude product of the previous step) was dissolved in 20mL of acetonitrile, DIEA (698 mg,5.4 mmol) and 6-cyano-1- (4-methoxybenzyl) -2-oxo-1, 2-dihydro-1, 5-naphthyridin-4-yl triflate (806 mg,1.8 mmol) were added, and the mixture was reacted at 80℃for 8 hours, and after the reaction was completed, the solvent was dried, stirred and subjected to column chromatography (ethyl acetate/petroleum ether=0 to 30%) to obtain 500mg of the product.
Preparation of 3.8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile
8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -5- (4-methoxybenzyl) -6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (240 mg,0.36 mmol) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.5 mL) was added dropwise and reacted at 15℃for 2 hours. After the reaction, the reaction solution is dripped into saturated sodium bicarbonate aqueous solution, dichloromethane extraction is carried out, an organic phase is collected, and the crude product of 200mg is obtained by drying and concentration.
Preparation of 6-cyano-4- ((2 s,5 r) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -1, 5-naphthyridin-2-yl triflate
8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (170 mg crude) was dissolved in 10mL of dichloromethane and DMAP (5 mg,0.04 mmol), triethylamine (121 mg,1.2 mmol) and Tf were added at 0deg.C 2 O (113 mg,0.4 mmol), at 0deg.C for 30 min, adding water for quenching, extracting with dichloromethane, collecting organic phase, and subjecting to column chromatography (petroleum ether: ethyl acetate=1:5) to obtain 280mg of product.
Preparation of tert-butyl 2- (6-cyano-4- ((2 s,5 r) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -1, 5-naphthyridin-2-yl) hydrazine-1-carboxylate
6-cyano-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -1, 5-naphthyridin-2-yl trifluoromethane sulfonate (250 mg,0.37 mmol), t-butoxycarbonyl hydrazine (58 mg,0.44 mmol), tris (dibenzylideneacetone) dipalladium (36 mg,0.04 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46 mg, 80.0. Mu. Mol) and cesium carbonate (244 mg,0.75 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted at 65℃for 2 hours under nitrogen protection. LCMS detects the end of the reaction. The solvent was concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:3) to give 180mg of the title compound, yield: 73.1%.
Preparation of 8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-hydrazino-1, 5-naphthyridine-2-carbonitrile
Tert-butyl 2- (6-cyano-4- ((2 s,5 r) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -1, 5-naphthyridin-2-yl) hydrazine-1-carboxylate (80 mg,0.12 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the addition was completed and reacted at 10 ℃ for 2 hours. LCMS detects the end of the reaction. The concentrate was used directly in the next step.
7.5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) - [1,2,4] triazolyl [4,3-a ] [1,5] naphthyridine-7-carbonitrile preparation (Compound 5)
8- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-hydrazino-1, 5-naphthyridine-2-carbonitrile (crude, 0.12 mmol) was dissolved in trimethyl orthoformate (2 mL) and reacted at 100℃for 1 hour. LCMS detects the end of the reaction. The solvent was concentrated and purified by silica gel plate (100% ethyl acetate) followed by pre-HPLC purification (acetonitrile/water=0-70%) to give the title compound 8.7mg, yield: 12.6%.
Molecular formula C 30 H 26 F 4 N 8 Molecular weight 574.6LC-MS (M/e): 575.1 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:9.10(s,1H),8.82(m,1H),8.40-8.37(m,1H),7.97-7.93(m,2H),7.80-7.77(m,1H),7.57-7.56(m,2H),7.13(m,1H),7.05-7.01(m,2H),5.10(s,1H),4.78(m,1H),3.67-3.65(m,1H),3.37-3.34(m,1H),3.17-3.14(m,1H),2.67-2.64(m,1H),2.52-2.49(m,1H),2.07-2.03(m,2H),1.88(m,3H),0.84-0.82(m,3H).
Preparation example 2: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) - [1,2,4] triazolyl [4,3-a ] [1,5] naphthyridine-7-carbonitrile (preparation of Compound 6)
Compound 6 was prepared according to the procedure of preparation 1, using intermediate 1A as starting material.
Molecular formula C 30 H 26 F 4 N 8 Molecular weight 574.6LC-MS (M/e): 575.1 (M+H) + )
Preparation example 3: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -7-fluoro- [1,2,4] triazolo [4,3-a ] quinazoline (Compound 11)
Preparation of 2-chloro-4- ((2 s,5 r) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoroquinazoline
(2R, 5S) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine (350 mg,0.92 mmol) (prepared from intermediate 1B) was dissolved in THF (10 mL) and 2, 4-dichloro-6-fluoroquinazoline (200 mg,0.92 mmol) and DIEA (362 mg,2.8 mmol) were added. After completion of the lcms reaction, the reaction was reacted at 50 ℃ for 2h and concentrated on silica gel column chromatography (MEOH: dcm=1:20) to give 200mg of the target compound in 38.7% yield.
Preparation of 4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-2-hydrazinoquinazoline
2-chloro-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoroquinazoline (150 mg,0.27 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (70 mg,1.4 mmol) was added, the reaction was carried out at 95℃for 3h, LCMS detection reaction was completed, and spin-drying was carried out to obtain 200mg of crude product.
Preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -7-fluoro- [1,2,4] triazolo [4,3-a ] quinazoline
4- ((2 s,5 r) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-2-hydrazinoquinazoline (200 mg, crude) was dissolved in trimethyl orthoformate (5 mL), stirred at 100 ℃ for 3h, and after completion of the reaction, dried by spin, silica gel column chromatography (methanol: dichloromethane=1:20) to give 18mg of the title compound in 11.8% yield.
Molecular formula C 28 H 26 F 5 N 7 Molecular weight: 567.6LC-MS (M/e): 568.1 (M+H) + )
1 H-NMR(400MHz,DMSO):δ:9.55(s,1H),8.82(s,1H),8.39-8.38(m,1H),8.21-8.19(m,1H),8.05-8.03(m,1H),7.90-7.89(m,1H),7.88-7.85(m,1H),7.61-7.60(m,2H),7.17-7.13(m,2H),4.45-4.44(m,1H),3.88-3.61(m,3H),3.09-3.02(m,1H),2.36-2.31(m,1H),1.99-1.97(m,1H),1.73-1.65(m,2H),1.30-1.28(m,3H),0.84-0.82(m,3H).
Preparation example 4: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -7-fluoro- [1,2,4] triazolo [4,3-a ] quinazoline (Compound 12)
Compound 12 was prepared in the same manner as in preparation example 3 using (2 r,5 s) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine (prepared from intermediate 1A) as a starting material.
Molecular formula C 29 H 26 F 5 N 7 Molecular weight 567.6LC-MS (M/e): 568.2 (M+H) + )
1 H-NMR(400MHz,DMSO):δ:9.56(s,1H),8.91(s,1H),8.39-8.38(m,1H),8.21-8.19(m,1H),7.97-7.95(m,1H),7.90-7.89(m,1H),7.88-7.85(m,1H),7.61-7.60(m,2H),7.17-7.13(m,2H),4.45-4.44(m,1H),3.88-3.61(m,3H),3.09-3.02(m,1H),2.36-2.31(m,1H),1.99-1.97(m,1H),1.73-1.65(m,2H),1.30-1.28(m,3H),0.84-0.82(m,3H).
Preparation example 5: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [2,3-e ] [1,2,4] triazolo [4,3-a ] pyrimidine-7-carbonitrile (Compound 17)
Preparation of 2, 6-dichloro-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [3,2-d ] pyrimidine
(2R, 5S) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine (100 mg,0.26 mmol) (prepared from intermediate 1B) was dissolved in 10mL of methylene chloride, DIEA (101 mg,0.78 mmol) and 2,4, 6-trichloropyrido [3,2-d ] pyrimidine (100 mg,0.36 mmol) were added, the reaction was carried out at 15℃for 2 hours, the solvent was dried by spin-drying, and the mixture was stirred and purified by column chromatography (ethyl acetate/petroleum ether=0 to 20%) to give 100mg of the product with a yield of 66.4%
Preparation of 2.6-chloro-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -2-hydrazinopyrido [3,2-d ] pyrimidine
2, 6-dichloro-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [3,2-d ] pyrimidine (100 mg,0.17 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (17 mg,0.34 mmol) was added dropwise for reaction at 80℃for 4 hours. After the reaction, the mixture was concentrated to give 100mg of crude product.
Preparation of 7-chloro-5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [2,3-e ] [1,2,4] triazolo [4,3-a ] pyrimidine
6-chloro-4- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) -2-hydrazinopyrido [3,2-d ] pyrimidine (100 mg crude product) was dissolved in 5mL trimethyl orthoformate, reacted at 100℃for 60 minutes, after the reaction was completed, concentrated, and column chromatography (methanol: dichloromethane=1:20) was performed to obtain 50mg of a product.
4.5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [2,3-e ] [1,2,4] triazolo [4,3-a ] pyrimidine-7-carbonitrile preparation
7-chloro-5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [2,3-e ] [1,2,4] triazolo [4,3-a ] pyrimidine (40 mg,0.07 mmol), zinc cyanide (16 mg,0.14 mmol), tris (dibenzylideneacetone) dipalladium (6 mg,0.007 mmol), DPPF (7 mg,0.014 mmol) and zinc powder (4 mg,0.07 mmol) were dissolved in 1, 4-dioxane (3 mL) and reacted at 150℃under nitrogen for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and purified on a silica gel column (methanol: dichloromethane=1:20) to give crude product, which was then subjected to pre-HPLC (acetonitrile/water 0-70%) to give 7.5mg of product in yield: 19.0%.
Molecular formula C 29 H 25 F 4 N 9 Molecular weight 575.6LC-MS (M/e): 576.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:8.87(s,1H),8.81(s,1H),8.34-8.32(m,1H),8.09-8.07(m,1H),7.93-7.91(m,1H),7.75-7.73(m,1H),7.58-7.55(m,2H),7.07-7.02(m,2H),5.40-5.35(m,1H),5.00(s,1H),3.70(m,1H),2.90-2.86(m,1H),2.65-2.56(m,2H),2.25-2.21(m,1H),1.73-1.68(m,5H),0.84-0.82(m,3H).
Preparation example 6: preparation of 5- ((2S, 5R) -5-ethyl-4- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylpiperazin-1-yl) pyrido [2,3-e ] [1,2,4] triazolo [4,3-a ] pyrimidine-7-carbonitrile (Compound 17)
Compound 17 was prepared according to the same method as in preparation example 5 using (2 r,5 s) -2-ethyl-1- ((4-fluorophenyl) (5- (trifluoromethyl) pyridin-2-yl) methyl) -5-methylpiperazine (prepared from intermediate 1A) as a starting material.
Molecular formula C 29 H 25 F 4 N 9 Molecular weight 575.6LC-MS (M/e): 576.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:8.87(s,1H),8.81(s,1H),8.34-8.32(m,1H),8.09-8.07(m,1H),7.93-7.91(m,1H),7.75-7.73(m,1H),7.58-7.55(m,2H),7.07-7.02(m,2H),5.40-5.35(m,1H),5.00(s,1H),3.70(m,1H),2.90-2.86(m,1H),2.65-2.56(m,2H),2.25-2.21(m,1H),1.73-1.68(m,5H),0.84-0.82(m,3H).
Using the same or similar methods as the preparation examples described above, the compounds shown in the following tables were prepared:
the DGK inhibitors provided by the invention and their use are described in detail above. The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to aid in the understanding of the method of the present invention and its central ideas. It should be noted that it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the principles of the invention, which also falls within the scope of the appended claims.
Claims (10)
1. A compound of the general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Wherein,,
X 1 、X 2 are independently selected from CR 4 Or N;
represents a single bond or is absent; when it indicates absence, X 3 Selected from C, CH or N; when representing a single bond, X 3 Is C;
ring A is selected from optionally 1 to 4Q 1 Substituted 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-8 membered heteroaryl; r is R 1 Selected from-CH 2 R a 、-CHR a R b 、-CR a R b R c or-NR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each R 4 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino,Nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each R a Each R b Each R c Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted C 1-6 Alkyl, C 1-6 Alkoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-8 membered heteroaryl, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m and each n are each independently an integer of 0 to 4;
each t is independently selected from 0, 1 or 2.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
X 1 、X 2 are independently selected from CR 4 Or N;
represents a single bond or is absent; when it indicates absence, X 3 Selected from C, CH or N; when representing a single bond, X 3 Is C;
ring A is selected from optionally 1 to 4Q 1 Substitution of5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; r is R 1 Selected from-CH 2 R a 、-CHR a R b 、-CR a R b R c or-NR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R 4 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R a Each R b Each R c Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted C 1-4 Alkyl, C 1-4 Alkoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-6 membered heteroaryl, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2.
3. The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has a structure represented by the general formula (II-1), the general formula (II-2), the general formula (II-3),
wherein,,
X 1 each independently selected from CH or N;
ring A is selected from optionally 1 to 3Q 1 Substituted 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;
R 1 selected from-CH 2 R a 、-CHR a R b ;
Each R 2 Each R 3 Are each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, halogen, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or C optionally substituted with 1-2 substituents 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each of said substituents being independently selected from carboxyl, cyano, hydroxy, nitro, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 1 Are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each R a Each R b Each independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 3Q 2 Substituted C 1-4 Alkyl, C 1-4 Alkoxy, each Q 2 Each independently selected from halogen, amino, hydroxy, carboxy, cyano,
or optionally 1 to 3Q 3 Substituted- (CH) 2 ) t -phenyl or- (CH) 2 ) t -a 5-6 membered heteroaryl; each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2;
Representing a single bond or the absence.
4. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claim 1 to 3, wherein,
ring A is selected from optionally 1 to 3Q 1 Substituted pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, tetrahydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2-dihydrothiazolyl, and the like,Phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl;
R 1 selected from-CH 2 R a or-CHR a R b ;
Each R 2 Each R 3 Independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, fluoro, chloro, bromo, iodo, -C (O) -R a 、-C(O)-NH-R a 、-C(O)OR a 、-NR a R b Or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridazinyl, oxazolyl, isoxazolyl or pyrazinyl optionally substituted with 1 to 2 substituents each independently selected from carboxy, cyano, hydroxy, nitro, amino, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each R 4 Each independently selected from hydrogen, carboxyl, cyano, hydroxyl, nitro, amino, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q 1 Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy or trifluoromethylFluoromethoxy;
each R a Each R b Each R c Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxy, carboxyl, cyano,
or optionally 1 to 4Q 2 Substituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, each Q 2 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano,
Or optionally 1 to 4Q 3 Substituted- (CH) 2 ) t -phenyl, - (CH) 2 ) t -5-6 membered heteroaryl, each Q 3 Each independently selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each m, each n is independently selected from 0, 1, 2 or 3;
each t is independently selected from 0, 1 or 2.
5. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claim 1 to 4, wherein,
R 1 selected from the following groups:
wherein Y is 1 、Y 2 Each independently selected from CH or N;
each R a Independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy radicalRadical, halogenated C 1-4 Alkyl or halo C 1-4 An alkoxy group;
each Q 3 Are each independently selected from halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy, - (CH) 2 ) t -3-6 membered cycloalkyl or- (CH) 2 ) t -3-6 membered heterocyclyl;
each p, each q is independently selected from 0, 1, 2 or 3.
6. The compound according to any one of claim 1 to 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has a structure represented by the general formula (III-1), the general formula (III-2), the general formula (III-3),
wherein,,
X 1 each independently selected from CH or N;
each Y 1 Each Y 2 Each independently selected from N or CH; each p, each q is independently selected from 0, 1 or 2;
ring A, each R 2 、R 3 、Q 1 Each Q 3 The method according to any one of claims 1 to 5.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the structure:
8. a pharmaceutical formulation comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
10. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical formulation according to claim 8, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or a related disease mediated by abnormal activity of dgkα, dgkζ or both dgkα and dgkζ; wherein the disease or related disease mediated by abnormal activity of DGK alpha, DGK zeta or both DGK alpha and DGK zeta is selected from cancer or benign tumor.
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